ABSTRACT Anxiety disorders are major causes of morbidity and in some cases, mortality, in the US population in general, and in the Veteran population, specifically. The goal of the proposed project is to identify genes influencing susceptibility for anxiety disorders, especially panic disorder (PD) and social phobia (SocP), and anxiety traits. In previous work we collected a set of anxiety disorder extended pedigrees ascertained through probands with PD, and completed genome wide linkage scans for several anxiety traits. Recently we focused on association paradigms, and identified RGS2 as a gene that can influence anxiety phenotypes, and CNTNAP2 as a gene that can affect selective mutism risk. We have also focused on posttraumatic stress disorder (PTSD), with several frequently-cited publications on GxE interaction and PTSD. In the past funding period, we were able to take advantage of a large sample of subjects recruited for NIH-funded substance dependence studies, in which we obtained comprehensive diagnostic information, including anxiety disorder diagnoses. We propose to continue our investigations in already-collected clinical material, and by continuing collection of a set of college-age subjects ascertained by Dr. Murray Stein (UCSD & San Diego VA) (presently, >1800 subjects). These are projects and collaborations of demonstrated productivity. Our prior efforts have left us with a good clinical resource for identifying anxiety disorder risk genes (1084 PD patients and 795 SocP patients, excluding subjects with those diagnoses in the San Diego sample).For this work we will employ control subjects already recruited via other NIH-funded projects: presently we have 1,020 screened European-American, and 832 screened African-American, control subjects. At VA Connecticut, we will collect 120 new SSADDA-ascertained DSM-IV PD and SocP subjects yearly, a total of 480 subjects - a recruitment rate consistent with what we have achieved previously. These subjects, together with PD and SocP subjects already ascertained and enumerated above, will leave us with an adequately-powered case-control sample. At UCSD, our collaborator will collect for each of the following 4 years: 150 students with range of anxiety-related traits measured, 20 patients with panic disorder, and 40 patients with SocP (i.e. 600 trait-anxiety subjects, 80 PD subjects, and 160 SocP subjects over the course of the project). This will leave us with a total of >2400 trait anxiety subjects. We have obtained preliminary SocP GWAS data based on a sample size of 250 affected (and a much larger set of unaffected). We propose to expand the social phobia GWAS by 300 additional subjects. This will still be a modest-sized sample, however, should provide interesting new leads, and provide the basis to permit genotyping of our full SocP sample (Years 1 and 2). In Years 3 and 4, we will accomplish exomic sequencing of 150 affected subjects (planning to compare these with at least 300 control subjects available elsewhere). We have completed exome sequencing for 20 PD samples, 12 selected from a single pedigree and 8 unrelated selected from 8 additional pedigrees. Our preliminary analysis of these data will prepare us for dealing with the large data set that will result from 150 additional subjects and data handling and analysis issues specific to next-gene sequencing. Finally, possibly-associated common variants (identified through GWAS) and rare variants (identified through exome sequencing) will be genotyped in the entire anxiety sample (categorical diagnoses and trait anxiety). This project has been highly productive to date, in its application of linkage and association paradigms to identify chromosomal regions likely to harbor genes influencing risk for anxiety disorders and for anxiety-related traits. Continuation of this work would build on the already-valuable sample collection and accumulation of knowledge and expertise on genetic analysis of anxiety disorders.